Sex hormone binding globulin and total testosterone levels are associated with in vivo tau burden differentially between the sexes: findings from the Framingham Study.

Background: In men and women, sex steroid hormones are associated with increased risk of Alzheimer's disease (AD) dementia. In older men, lower levels of testosterone are associated with higher rates of AD dementia. The relationship between estradiol levels on AD dementia risk in post‐menopausal women, however, is less clear, with studies reporting protective, deleterious and no effects. Finally, higher levels of sex hormone binding globulin (SHBG), a glycoprotein that regulates, and actively influences sex hormones, has been consistently linked with increased risk for AD dementia. Studies have yet to examine mid‐life hormonal levels in association with later‐life in vivo AD biomarkers in cognitively healthy adults. Method: 175 women and 159 men from the Framingham Study 3rd Generation cohort underwent blood (hormones) collection in 2002‐2005, and 18F‐Flortaucipir (FTP)‐PET and 11C‐PiB‐PET scans in 2016‐2020 (Table1). We examined FTP‐PET signal (referenced to cerebellar grey) in six a priori regions that previously demonstrated sex differences (entorhinal, inferior temporal, rostral middle frontal, inf/sup parietal and lateral occipital). Linear regressions examined sex‐stratified analyses of free/total testosterone, estradiol, and SHBG in each region, adjusting for age, age2, PET camera and plasma‐PET date‐difference (mean = 15(±2)yrs). Separate models examined interactions with a neocortical PiB‐PET composite and APOEε4. Result: In men, elevated SHBG was associated with lower FTP‐PET in entorhinal (p = 0.007), inferior temporal (p = 0.04) and rostral middle frontal regions (p = 0.02; Table2). Higher total testosterone was marginally associated with lower FTP‐PET signal in the latter region (p = 0.06), but other relationships were apparent. In women, higher total testosterone associated with lower FTP‐PET signal in inferior temporal (p = 0.05) and parietal regions (p = 0.04). Women APOEε4 carriers with higher estradiol showed higher levels of entorhinal FTP‐PET signal (p = 0.03;Table3). Conclusion: Higher levels of SHBG are associated with lower risk of AD‐related comorbidities, such as osteoporosis, diabetes, and visceral weight gain. A strong link between higher SHBG levels and higher HDL‐cholesterol may suggest a potential protective cardiovascular pathway for men against higher tau burden later in life. A lack of protective effect of pre‐menopausal estradiol in female APOEε4 carriers supports the notion that the role of estrogen in AD risk is centered around timing of decline. [ABSTRACT FROM AUTHOR]